Protein S deficiency has long been recognized as a leading risk factor for developing venous thromboembolism. Manufactured in the liver, protein S is an endogenous anticoagulant required as a cofactor for the protein C pathway, an important inhibitor system in coagulation. Whether contracted congenitally or acquired secondarily to numerous underlying disorders or therapies, this deficiency can potentially lead to venous thrombosis and life-threatening complications such as pulmonary embolism.